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    Summary
    EudraCT Number:2012-001457-50
    Sponsor's Protocol Code Number:SIL-TH-01
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-04-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-001457-50
    A.3Full title of the trial
    Study on the effect of intravenous silimaryn in the perioperative period of liver transplantation (before, during and after) for the prevention and prognosis of hepatitis C virus reinfection of the graft.
    Estudio del tratamiento con silimarina intravenosa (iv) en el periodo peritrasplante hepático (antes, durante y después) en la prevención de la infección del nuevo injerto e influencia en el pronóstico de la reinfección por VHC
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intravenous Silimaryn in hepatitis C Liver Trasplantation
    Silimarina intravenosa en trasplante hepático
    A.4.1Sponsor's protocol code numberSIL-TH-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorfUNDACIÓN iNVESTIGACIÓN HOSPITAL RAMÓN Y CAJAL
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportISCIII
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundación Investigación Biomédica Hospital Ramón y Cajal
    B.5.2Functional name of contact pointFundación Investigación
    B.5.3 Address:
    B.5.3.1Street AddressCTRA de Colmenar Viejo KM 9,100
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28034
    B.5.3.4CountrySpain
    B.5.4Telephone number0034133688258825
    B.5.5Fax number0034133688258825
    B.5.6E-mailipablo.hrc@salud.madrid.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Legalon SIL
    D.2.1.1.2Name of the Marketing Authorisation holderROTTAPHARM
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLEGALON SIL
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLegalon SIL
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients transplanted for chronic liver disease or hepatocarcinoma relating to C virus being replicated at the time of the OLT (orthotopic liver transplantation).
    pacientes sometidos a trasplante hepático secundario a hepatocarcinoma por VHC
    E.1.1.1Medical condition in easily understood language
    Patients transplanted for chronic liver disease and hepatitis C infection
    pacientes sometidos a trasplante hepatico con infección por el virus de la hepatitis C
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Study if treatment with intravenous Silymarin during perioperative OLT prevents graft infection and hepatitis virus C recurrence, in positive HCV patients.
    Estudiar si el tratamiento con silimarina intravenosa en el periodo peritrasplante impide la infección del injerto y la recidiva de la hepatitis por virus C, en pacientes VHC positivos trasplantados de hígado.
    E.2.2Secondary objectives of the trial
    Study the antiviral effect of intravenous Silymarin during perioperative OLT period on hepatitis C virus in positive HCV patients transplanted liver in the pattern used in our study.
    Determine if there is a relationship between IL-28 polymorphisms and response to treatment.
    Studying possible mutations in the virus-polymerase secondary to use of Silymarin.
    Estudiar el efecto antivírico de la silimarina intravenosa en el periodo peritrasplante sobre el virus de la hepatitis C en pacientes VHC positivos trasplantados de hígado, en la pauta utilizada en nuestro estudio.
    Determinar si existe relación entre los polimorfismos de IL-28 y la respuesta al tratamiento.
    Estudiar posibles mutaciones en la polimerasa del virus secundarias al uso de silimarina.
    Seguridad del tratamiento con silimarina
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients having receivesd written property information about the study design, endpoints and possible risks and they are able to refuse their consent at any time, give their consent to participate and supply of samples for celular and molecular studies
    Patients infected with the virus of hepatitis C.
    HCV-positive candidates in whom who the indication of liver transplantation is one of the globally accepted (hepatocellular and/or a HCC and/or alcohol failure).
    Women of childbearing potential must have a negative pregnancy test at screening visit. Futher agree to use adequate contraception (including double barrier as condoms plus diaphrams, or surgical sterilization) whitin 30 days after administration of study drug.
    - Pacientes, que tras haber recibir información sobre el diseño, los fines del estudio, los posibles riesgos que de él pueden derivarse y de que en cualquier momento pueden denegar su colaboración, otorguen por escrito su consentimiento para participar en el estudio y para la cesión de material para estudios celulares y moleculares.
    - Mayores de 18 años.
    - Pacientes candidatos a trasplante hepático infectados por el virus de la hepatitis C.
    - Pacientes virus C positivos, en los que la indicación del trasplante sea una de las globalmente aceptadas (insuficiencia hepatocelular y/o hepatocarcinoma y/o alcohol).
    - Las mujeres en edad fértil deberán obtener un resultado negativo en la prueba de embarazo en la visita de selección; además se comprometen a utilizar un método anticonceptivo adecuado (entre ellos se consideran: doble barrera como preservativo + diafragma, esterilización quirúrgica) durante la administración del fármaco en estudio y un mes posterior.
    E.4Principal exclusion criteria
    Refusal of informed consent.
    Contraindication for liver transplantation.
    Patient undergoing multiple organ transplantation.
    Hepatitis B virus-coinfected patient.

    Pregnacy or planning to become pregnant during the study.
    Lactation.
    - Denegación del consentimiento informado.
    - Contraindicación para el trasplante hepático.
    - Paciente sometido a trasplante multiorgánico.
    - Paciente coinfectado con el virus de la hepatitis B.
    - Embarazo o planificación de quedarse embarazada durante el transcurso del estudio.
    - Lactancia
    E.5 End points
    E.5.1Primary end point(s)
    HCV RNA: We will determinate IT before anaesthetic induction, anhepatic phase, every 6 hours in 24 hours after OLT and on days 1, 3, 5, 7 and 14 after OLT. If RNA becomes negative, it should be determined on the 21, 28, 35, 42 Y 49 days, the third month and 6 months to demonstrate VSR.
    If HCV fails to reach clearance viral load determinations will taken on 21 and 28 days after OLT and thereafter according to clinical protocol.
    Shall be considered as infection (SVR) has been avoided if the patient remains undetectable HCV RNA at least 6 months after completion of treatment with Silymarin and in the absence of other treatments for hepatitis C infection.
    ARN VHC: Se determinará el antes de la inducción anestésica, en la fase anhepática, cada 6 horas en las primeras 24 horas postrasplante y en los días 1, 3, 5, 7 y 14 posttrasplante hepático. Si el ARN fuera negativo, se determinará a los 21, 28, 35, 42 y 49 días, al tercer mes y a los 6 meses para demostrar RVS.
    Si el VHC no se negativiza se continuarán las determinaciones de la carga vírica a los 21 y 28 días postrasplante y posteriormente según protocolo del centro.
    Se considerará que se ha evitado la reinfección (RVS) si el paciente mantiene ARN del VHC indetectable al menos 6 meses después de la finalización del tratamiento con silimarina y en ausencia de otros tratamientos para la infección de VHC.
    E.5.1.1Timepoint(s) of evaluation of this end point
    DAY 1, 3, 5, 7 and 14 post liver tranplantation. If Negative RNA on day 14: 21, 28, 32, 42 and 49 days
    1, 3, 5, 7 y 14 DIAS posttrasplante hepático. Si el ARN fuera negativo, se determinará a los 21, 28, 35, 42 y 49 días
    E.5.2Secondary end point(s)
    -Patients will be evaluated daily by one of the clinical cares participants in the study in order to assess the occurrence of possible side or adverse effects of treatment. A physical examination and appropriate anamnesis will be perform and determined daily or every 48 hours values of creatinine, transaminases, bilirubin, GGT and FA, hemoglobin, hematocrit, platelet and leukocytes count, prothrombin, activity time cefalina and INR, as well as monitoring of blood levels of immunosuppressants (those which use monitoring) and other analytical determinations considered necessary.
    - DNA-CMV will be determinate according to each centre protocol and the histological results of biopsies made by protocol or indication will be shown in the final data.
    - IL-28 polymorphisms, both donor and recipient, as well as the possible occurrence of HCV polymerase-mutations will be determined during the duration of the study.
    -To determine the occurrence of resistant forms or the existence of basal resistant forms we will discuss in this region through RT-PCR and sequencing with BigDye viral RNA terminator v. 3.1 (Applied Biosistems) prior to treatment serum in subsequent samples in cases with signs of resurgence of viral load or not respondents.
    Efectos adversos del tratamiento. Los pacientes serán evaluados diariamente por uno de los facultativos participantes en el estudio a fin de valorar la aparición de posible Se realizará una exploración física y anamnesis adecuadas y se determinarán diariamente o cada 48 horas los valores de creatinina, transaminasas, bilirrubina, GGT y FA, hemoglobina, hematocrito, plaquetas, leucocitos y fórmula, actividad de protrombina, tiempo de cefalina e INR. Se realizará la monitorización de los niveles sanguíneos de los fármacos inmunosupresores (aquellos en los que se use monitorización) y otras determinaciones analíticas que se consideren necesarias.
    - Se monitorizará igualmente el DNA del CMV según protocolo de nuestro centro y el resultado histológico de las biopsias que se realicen por protocolo en cada centro o a indicación del médico responsable del paciente.
    - Se determinarán los polimorfismos de IL-28 tanto del donante como del receptor, así como la posible aparición de mutaciones de la polimerasa del VHC durante la duración del estudio.
    - Para determinar la aparición de formas resistentes o la existencia de formas resistentes basales analizaremos en ARN viral de esta región mediante RT-PCR y secuenciación con BigDye terminator v. 3.1 (Applied Biosistems) en el suero previo al tratamiento y en muestras posteriores en casos con indicios de rebrote de carga viral o no respondedores.
    E.5.2.1Timepoint(s) of evaluation of this end point
    DAY 1, 3, 5, 7 and 14 post liver tranplantation. If Negative RNA on day 14: 21, 28, 32, 42 and 49 days
    1, 3, 5, 7 y 14 DIAS posttrasplante hepático. Si el ARN fuera negativo, se determinará a los 21, 28, 35, 42 y 49 días
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The clinical trial will finish after the last visit of the lastest enrolled patient
    La última visita del último paciente reclutado en el estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The expected normal treatment for theese patients
    El tratamiento habitual en este tipo de pacientes
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-23
    P. End of Trial
    P.End of Trial StatusOngoing
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